The characteristics of mesenteric adipose tissue attached to different intestinal segments and their roles in immune regulation

Background: Mesenteric adipose tissue (MAT) plays a critical role in the intestinal physiological ecosystems. Small and large intestines have evidently intrinsic and distinct characteristics. However, whether there exist any mesenteric differences adjacent to the small and large intestines (SMAT and LMAT) has not been properly characterized. We studied the important facets of these differences, such as morphology, gene expression, cell components and immune regulation of MATs, to characterize the mesenteric differences. Methods: The SMAT and LMAT of mice were utilized for comparison of tissue morphology. Paired mesenteric samples were analyzed by RNA-seq to clarify gene expression profiles. MAT partial excision models were constructed to illustrate the immune regulation roles of MATs, and 16S-seq was applied to detect the subsequent effect on microbiota. Results: Our data show that different segments of mesenteries have different morphological structures. SMAT not only has smaller adipocytes but also contains more fat-associated lymphoid clusters than LMAT. The gene expression profile is also discrepant between these two MATs in mice. B-cell markers were abundantly expressed in SMAT, while development-related genes were highly expressed in LMAT. Adipose-derived stem cells of LMAT exhibited higher adipogenic potential and lower proliferation rates than those of SMAT. In addition, SMAT and LMAT play different roles in immune regulation and subsequently affect microbiota components. Finally, our data clarified the described differences between SMAT and LMAT in humans. Conclusions: There were significant differences in cell morphology, gene expression profiles, cell components, biological characteristics, and immune and microbiota regulation roles between regional MATs.

Microbiota in mesenteric adipose tissue from Crohn’s disease promote colitis in mice

Background Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat is a pathologic characteristic of Crohn’s disease (CD). The reserve of creeping fat in surgery is associated with poor prognosis of CD patients, but the mechanism remains unknown. Methods Mesenteric microbiome, metabolome, and host transcriptome were characterized using a cohort of 48 patients with CD and 16 non-CD controls. Multidimensional data including 16S ribosomal RNA gene sequencing (16S rRNA), host RNA sequencing, and metabolome were integrated to reveal network interaction. Mesenteric resident bacteria were isolated from mAT and functionally investigated both in the dextran sulfate sodium (DSS) model and in the Il10 gene-deficient (Il10−/−) mouse colitis model to validate their pro-inflammatory roles. Results Mesenteric microbiota contributed to aberrant metabolites production and transcripts in mATs from patients with CD. The presence of mAT resident microbiota was associated with the development of CD. Achromobacter pulmonis (A. pulmonis) isolated from CD mAT could translocate to mAT and exacerbate both DSS-induced and Il10 gene-deficient (Il10−/−) spontaneous colitis in mice. The levels of A. pulmonis in both mAT and mucous layer from CD patients were higher compared to those from the non-CD group. Conclusions This study suggests that the mesenteric microbiota from patients with CD sculpt a detrimental microenvironment and promote intestinal inflammation.

Microbiota in Mesenteric Adipose Tissue From Crohn’s Disease Promote Colitis in Mice

Background: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat is a pathologic characteristic of Crohn’s disease (CD). The reserve of creeping fat in surgery is associated with poor prognosis of CD patients, but the mechanism remains unknown.Methods: Mesenteric microbiome, metabolome and host transcriptome were characterized using a cohort of 48 patients with CD and 16 non-CD controls. Multidimensional data including 16S ribosomal RNA gene sequencing (16S rRNA), host RNA sequencing and metabolome were integrated to reveal network interaction. Mesenteric resident bacteria were isolated from mAT and functionally investigated both in dextran sulfate sodium (DSS) model and Il10 gene deficient (Il10-/-) mouse colitis model to validate their pro-inflammatory roles. Results: Mesenteric microbiota contributed to aberrant metabolites production and transcripts in mATs from patients with CD. Presence of mAT resident microbiota was associated with the development of CD. Achromobacter pulmonis (A. pulmonis) isolated from CD mAT could translocate to mAT and exacerbate both DSS-induced and Il10 gene deficient (Il10-/-) spontaneous colitis in mice. The levels of A. pulmonis both in mAT and mucous layer from CD patients were higher compared to those from non-CD group. Conclusions: This study suggests that the mesenteric microbiota from patients with CD sculpt a detrimental microenvironment and promote intestinal inflammation.

Debilitating Manifestation of a Disease with Multiple Names: A Severe Case of Sclerosing Mesenteritis

Sclerosing mesenteritis (SM) is a rare inflammatory condition with unknown etiology that affects the mesenteric adipose tissue. We present a case of a 49-year-old male with severe abdominal pain who underwent abdominal biopsy confirming the presence of adipose inflammation and necrosis. The diagnosis of SM was made, and the patient was treated with prednisone and tamoxifen. As this condition is rare, there are no standard guidelines for management. This case aims to outline a possible treatment plan.

Expression of clock gene Dbp in omental and mesenteric adipose tissue in patients with type 2 diabetes

IntroductionWe previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity.Research design and methodsThe present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2).ResultsAcetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue.ConclusionsThe changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.

Disturbance of Fatty Acid Desaturation Mediated by FADS2 in Mesenteric Adipocytes Contributes to Chronic Inflammation of Crohn’s Disease

Background and Aims The aim of this study was to investigate the metabolic profile of mesenteric adipocytes and the correlations between key metabolic changes and local inflammation in the context of Crohn’s disease [CD]. Methods Metabolic dysfunction was shown to be regulated by fatty acid desaturase-2 [FADS2], through metabolomics and functional analyses of mesenteric adipose tissue biopsies and primary mesenteric adipocytes isolated from surgical specimens collected from CD patients and control subjects. FADS2 was overexpressed in vitro and in vivo using a lentiviral vector and an adeno-associated virus [AAV], respectively. The interaction between mesenteric adipocytes and inflammation responses was evaluated by establishing a cell coculture system and a FADS2-AAV treated animal model; 3T3-L1 cells were used to elucidate the mechanism underlying FADS2 deregulation. Results We observed significant changes in the levels of metabolites involved in the multi-step synthesis of long-chain polyunsaturated fatty acids [PUFAs]. Gas chromatography analysis revealed impaired desaturation fluxes towards the n-6 and n-3 pathways, which are associated with reduced FADS2 activity in human mesentery tissue. Decreased FADS2 expression at both mRNA and protein levels was confirmed in surgical specimens. The restoration of FADS2 expression, which allows for the endogenous conversion of n-3 fatty acids into proresolving lipid mediators, resulted in a significant reduction in pro-inflammatory macrophage infiltration and attenuated expression of inflammatory cytokines or adipokines. Conclusions These findings indicate that impaired fatty acid desaturation and lipid mediator imbalance within mesenteric adipose tissue contributes to chronic inflammation in CD. The therapeutic role of FADS2 may lead to improved CD treatment.

Role of Obesity, Mesenteric Adipose Tissue, and Adipokines in Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs) are a group of disorders which include ulcerative colitis and Crohn’s disease. Obesity is becoming increasingly more common among patients with inflammatory bowel disease and plays a role in the development and course of the disease. This is especially true in the case of Crohn’s disease. The recent results indicate a special role of visceral adipose tissue and particularly mesenteric adipose tissue, also known as “creeping fat”, in pathomechanism, leading to intestinal inflammation. The involvement of altered adipocyte function and the deregulated production of adipokines, such as leptin and adiponectin, has been suggested in pathogenesis of IBD. In this review, we discuss the epidemiology and pathophysiology of obesity in IBD, the influence of a Western diet on the course of Crohn’s disease and colitis in IBD patients and animal’s models, and the potential role of adipokines in these disorders. Since altered body composition, decrease of skeletal muscle mass, and development of pathologically changed mesenteric white adipose tissue are well-known features of IBD and especially of Crohn’s disease, we discuss the possible crosstalk between adipokines and myokines released from skeletal muscle during exercise with moderate or forced intensity. The emerging role of microbiota and the antioxidative and anti-inflammatory enzymes such as intestinal alkaline phosphatase is also discussed, in order to open new avenues for the therapy against intestinal perturbations associated with IBD.

β-Cryptoxanthin Prevents Non-alcoholic Fatty Liver Disease Through Different Mechanisms Depending on the Presence or Absence of Carotenoid Cleavage Enzymes (FS06-03-192)

Objectives β-Cryptoxanthin (BCX), a provitamin A carotenoid, is cleaved by carotenoid cleavage enzymes including β-carotene-15, 15′-oxygenase (BCO1) to generate vitamin A, and β-carotene-9′, 10′-oxygenase (BCO2) which yields bioactive apo-carotenoids. Dietary supplementation of BCX can prevent non-alcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide. This study aimed to investigate whether BCX-mediated protection against NAFLD proceeds through the liver-mesenteric adipose tissue axis depending on the presence or absence of BCO1/BCO2. Methods Six-week-old male wild type (WT) mice (n = 30) and congenic BCO1−/−/BCO2−/− double KO (DKO) mice (n = 30) were randomly fed either a high-refined carbohydrate diet (HRCD, 66.5% CHO) or HRCD with BCX (10 mg/kg diet) for 24 weeks. Results Hepatic levels of BCX, but not retinol and retinyl palmitate, were significantly (P < 0.001) higher (33-fold) in the DKO mice than in the WT mice. BCX significantly reduced hepatic steatosis and total cholesterol levels in both WT and DKO mice in comparison with their HRCD counterparts (P < 0.01 and P < 0.001, respectively), albeit through different mechanisms. In the liver, BCX significantly (P < 0.05) down-regulated mRNA for cholesterol synthesis genes Hmgcr and Hmgs1 and nuclear bile acid receptor Fxr, and up-regulated cholesterol catabolism gene Cyp7a1 in DKO mice in comparison with their HRCD counterparts. Furthermore, BCX significantly (P < 0.05) up-regulated antioxidant enzymes Sod1 and Cat in DKO mice in comparison with HRCD littermates. In WT mice, BCX significantly (P < 0.05) up-regulated hepatic mRNA for cholesterol efflux gene Abcg5 and nuclear receptor Shp in comparison with their HRCD counterparts. In mesenteric adipose tissue, BCX significantly down-regulated (P < 0.05) the inflammatory cytokine Il6 and up-regulated fatty acid β-oxidation marker Acox1 and Sirt1 in DKO mice but significantly (P < 0.05) suppressed lipogenesis marker Acc1 in WT mice. Conclusions The protective effects of dietary BCX against HRCD-induced NAFLD are achieved through different molecular mechanisms in the liver-mesenteric adipose tissue axis and depend on the carotenoid cleavage enzymes. Funding Sources NIFA/AFRI (2017-67017-26363) and USDA/ARS (58-1950-0074).